Experimental non-ATP-competitive therapies for chronic myelogenous leukemia.

Abstract

Chronic myelogenous leukemia (CML) is a hematopoietic stem cell malignancy driven by the BCR-ABL fusion tyrosine kinase. The central role played by BCR-ABL1 in the pathogenesis of CML facilitated the development of the tyrosine kinase inhibitor (TKI) imatinib mesylate, the first actual targeted therapy in cancer history. Imatinib competes with ATP at the active site of BCR-ABL1 kinase. Despite outstanding clinical results, imatinib as well as other BCR-ABL1 TKIs have been associated with limited rates of complete molecular response and the development of mutations within the kinase domain of BCR-ABL1 that impairs TKI binding. To override such drawbacks, an array of novel non-ATP-competitive therapies with distinct mechanisms of action is undergoing preclinical, and in some cases, early clinical stages of development. This review focuses on the most promising among such therapeutics.